Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States. PDA is almost universally fatal in part due to the high rate of metastasis at the time of detection. Athough patients die from metastatic disease rather than from the primary tumor, relatively little is known regarding the transition from carcinoma in situ to metastatic disease. The main objective of this proposal is to identify genetic lesions associated with the development of metastatic disease. Utilizing a mouse model that harbors an endogenous, conditionally-expressed, oncogenic K-ras G12D allele and/or a mutant p53 allele, tumors will be uniquely tagged to facilitate lineage tracing analysis. Lineage tracing will enable comparison of primary tumors and descendant metastases with genetic certainty, thus allowing genomic, transcriptomic, and proteomic profiling analyses to identify candidate genes associated with metastasis. These candidate genes will then be validated in both human pancreatic cancer cell lines and primary human tumor samples. [unreadable] [unreadable] [unreadable] [unreadable]